with radical neck dissection followed by radiotherapy to the tumour bed and chemotherapy [36, 145]. The recent identification of androgen receptors expression in SDC raises the question as to whether anti-androgen therapy (e.g. flutamide or goserelin) might have merit [99, 142, 153]. The significance of staining for HER-2/neu (c-erbB-2) protein is at present uncertain [202, 204], either prognostically or for planning therapy with herceptin.
The entity "low grade salivary duct carcinoma (low grade cribriform cystadenocarcinoma)" has a predominantly intraductal growth pattern with low-grade cyto-logical features , and its relationship to usual-type SDC is as yet uncertain. The tumour is S-100-positive and the only case studied for AR was negative . The prognosis is good, and although only a few cases have been described, none of the patients has died of disease.
5.9.10 Oncocytic Carcinoma
Several carcinoma types have variants composed of oncocytic cells, but only a few dozen cases of pure on-cocytic carcinoma have been reported. The average age is 63 years (range 29-91), and most have occurred in the parotid ; some have arisen in Warthin's tumours . The diagnosis of a pure oncocytic carcinoma requires the identification of malignancy, oncocytic differentiation and lack of features of any other tumour type. It is likely that a pure oncocytic carcinoma is an aggressive tumour, as over half of the patients reported either died of disease or suffered recurrences .
5.9.11 Malignancy in Pleomorphic Adenoma Malignant Mixed Tumour overall, malignancy develops in 6.2% of all PAs (range in different series 1.9 to 23.3%). The incidence of malignant change increases with the length of history of the PA, from 1.5% at 5 years to 10% after 15 years. The concept of malignant mixed tumour (MMT) as a malignant tumour that contains remnants of benign mixed tumour was developed by LiVolsi and Perzin in 1977 . Spiro et al.  agreed with this, but suggested a possible de novo origin in cases lacking a clinical history or histological evidence of a pre-existing salivary gland tumour.
The revised WHO classification of salivary gland tumours  discussed the topic of MMT with the title Carcinoma in Pleomorphic Adenoma and the sub-title Malignant Mixed Tumour. Three entities are recognised: carcinoma in pleomorphic adenoma, carcinosarcoma (true malignant mixed tumour) and metastasising pleo-morphic adenoma . There is no uniform agreement on this classification as metastasising PA does not contain histological features of malignancy and therefore it is anomalous to include it as a form of malignancy in PA. In addition, not all carcinosarcomas arise from a PA. Finally, the possibility of myoepithelial malignancy arising in a PA is not included .
Ex Pleomorphic Adenoma
Two subtypes should be recognised: invasive and non-invasive carcinoma.
The histological diagnosis of pleomorphic adenoma (PA; benign mixed tumour) is not always straightforward, as benign lesions may display atypical histologic features such as capsular infiltration, hypercellularity, cellular atypia, necrosis and vascular invasion [3, 7], which cause suspected malignancy. In addition, some PAs contain genuine cytologically malignant cells, but behave in a benign fashion [21, 56]. A further paradox is the rare occurrence of histologically benign-looking PAs that metastasise . Thus, the concept of malignancy in PA is much more complex than appears at first sight. This is reflected by the variable incidence for the reported frequency of malignancy in PA. In several large series [83, 125, 149, 209, 223] the average was 3.6% of all salivary gland tumours and 11.7% of malignancies;
This is the commoner form, in which the malignancy involves only the epithelial component. It occurs mainly in men over 60 years old. Most cases (81.7%) involve the parotid gland, with the submandibular in 18% and the sublingual in 0.3%; the minor salivary glands, particularly in the palate, can also be affected . The typical presentation is a long history of a salivary gland nodule that suddenly increases in size.
The demonstration of both a carcinoma and a PA is necessary for the diagnosis.
A history of a long-standing parotid tumour is not sufficient evidence for a pre-existing PA, whilst a previously excised PA at the site of a carcinoma is acceptable .
Grossly, carcinoma ex PA is often larger than a benign PA. Histological recognition of a pre-existing PA may be difficult, as it could be obscured by the carcinoma, or may only show degenerate changes such as
scarring, dystrophic calcification, necrosis and haemorrhage with occasional transitional changes made up of cells showing features intermediate between frank malignancy and PA [49, 124]. Although the proportion of the malignant component varies from minute foci to almost the whole lesion, recognition of frankly invasive carcinoma ex PA is usually simple. Capsular, perineural and vascular invasion are easily identified, as well as extension into neighbouring tissues [49, 62, 124].
Recent studies show adenocarcinoma not otherwise specified and salivary duct carcinoma to be the most frequent histological types [49, 87], and there is immunohistochemical and ultrastructural evidence that many carcinomas previously described as "undif-ferentiated" are in fact myoepithelial - indeed many myoepithelial carcinomas can be shown to have arisen in a pre-existing PA [52, 53, 151, 168]. It is not uncommon to find other concurrent differentiation, e.g. squamous, mucoepidermoid, polymorphous low-grade adenocarcinoma [125, 149, 209]. In determining the prognosis, the extent of invasion is more important than the histological type: Tortoledo et al.  found that none of the patients whose tumour penetrated <6 mm beyond the capsule died of disease, but that all patients with invasion of >8 mm died of disease. A more recent study found that none of the tumours that invaded <5 mm beyond the host PA progressed .
In contrast to the aggressive behaviour of invasive carcinoma ex PA, tumours that contain only circumscribed areas of malignancy confined within the capsule  behave in a benign fashion after excision (Fig. 5.51). In one series, four patients with intracapsular (non-invasive) carcinoma all had a good clinical outcome . Brandwein et al.  confirmed this and also noted that the same benign behaviour applies for minimally invasive carcinoma ex PA. In contrast, there is a single report of metastases developing from a non-invasive carcinoma . In spite of the generally excellent behaviour, the cells in non-invasive carcinoma ex PA display overexpression and amplification of HER-2/neu protein, and thus probably represent true carcinoma in an early phase rather than just bizarre cytological changes . This study also recommended the use of HER-2/neu immunohistochemistry to distinguish between PAs with atypical cells and non-invasive carcinoma ex PA .
(True Malignant Mixed Tumour) Ex Pleomorphic Adenoma
Only about 60 cases of carcinosarcoma (CS) true malignant mixed tumour (TMMT) have been reported to date [83, 214]. Many arise in a pre-existing PA, but they can also develop de novo. As with carcinoma in a PA,
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